Compositions and devices for controlled release of active ingredients

ABSTRACT

A method for the controlled release of a biologically active agent wherein the agent is released from a hydrophobic, pH-sensitive polymer matrix is disclosed and claimed. In one embodiment, the polymer matrix swells when the environment reaches pH 8.5, releasing the active agent. A polymer of hydrophobic and weakly acidic comonomers is disclosed for use in the controlled release system. In another embodiment, weakly basic comonomers are used and the active agent is released as the pH drops. Further disclosed is a specific embodiment in which the controlled release system may be used. The pH-sensitive polymer is coated onto a latex catheter used in ureteral catheterization. A common problem with catheterized patients is the infection of the urinary tract with urease-producing bacteria. In addition to the irritation caused by the presence of the bacteria, urease produced by these bacteria degrade urea in the urine, forming carbon dioxide and ammonia. The ammonia causes an increase in the pH of the urine. Minerals in the urine begin to precipitate at this high pH, forming encrustations which complicate the functioning of the catheter. A ureteral catheter coated with a pH-sensitive polymer having an antibiotic or urease inhibitor trapped within its matrix releases the active agent when exposed to the high pH urine as the polymer gel swells. Such release can be made slow enough so that the drug remains at significant levels for a clinically useful period of time. Other uses for the methods and devices of this invention include use in gastrointestinal tubes, respiratory trap lines and ventilation tubes, dye releasing pH sensitive sutures, active agent release from contact lenses, penile implants, heart pacemakers, neural shunts, food wraps, and clean room walls.

CROSS-REFERENCE TO A RELATED APPLICATION

This application is a continuation-in-part of application Ser. No.08/382,315, filed Feb. 1, 1995 now U.S. Pat. No. 5,607,417, which is acontinuation-in-part of application Ser. No. 08/189,854, filed Feb. 1,1994, now U.S. Pat. No. 5,554,147.

DESCRIPTION Background of the Invention

The term "controlled release" refers generally to techniques foradministering an agent wherein the agent is released in a certain manneraffecting either the location or the timing of the release. Controlledrelease techniques have particular advantages in the context ofadministering therapeutic agents. For example, the release rate of adrug can be predicted and designed for an extended duration; thiseliminates problems associated with patients neglecting to take requiredmedication in specified dosages at specified times. Many drugs haveshort half-lives in the body before being removed. Trapping these drugsin polymeric matrices increases the time in which the drug maintains itsactivity. Further, the site specific localization of a drug achievedwith a targeted delivery technique reduces or eliminates systemic sideeffects that certain medications cause when administered orally orintravenously.

There are several general types of controlled release systems. Forexample, drug release can be diffusion controlled, meaning that thediffusion of the agent trapped within a polymer matrix is therate-determining factor for the overall release rate. Erosion basedsystems also exist in which a polymer degrades over time and releases adrug in an amount proportional to the gradual erosion. An osmoticpumping device uses osmotic pressure as the driving force for release. Afourth system is based on the swelling of a polymeric matrix, such as ahydrogel. Hydrogels are polymers that absorb and swell in an aqueousenvironment. The release of the agent is dependent on the volumeincrease of the gel upon swelling and is then diffusion controlled.

One mechanism which utilizes swelling for controlled release involvesthe movement of a solvent into a polymer matrix. The solvent must bethermodynamically compatible with the polymer. The solvent moves towardthe core of the matrix at a constant velocity, which is a factor indetermining the release rate of the solute drug (Ritger and Peppas,1987). The penetration of the matrix creates stresses between polymerchains. In order to accommodate these stresses, the chains respond bymoving and increasing their end-to-end distance. This response causes alowering of the polymer's glass transition temperature (T_(g)), and meshsize (free volume between the chains) increases to swell the polymer.The increased mesh and increased mobility of the chains in the swollenregion result in increased permeability of the polymer to the solvent(Korsmeyer and Peppas, 1984). In pH sensitive polymers, the pH of theenvironment influences the release rate of the solute by affecting theswelling behavior of the gel (Brannon-Peppas and Peppas, 1989).

One context in which the use of controlled release systems has beeninvestigated involves the treatment of urinary tract infectionsassociated with ureteral catheters or stents. The ureter functions as apathway for urine leading from the kidney to the bladder. Obstruction ofthe ureter requires the placement of a ureteral stent to open thepathway and assist in the passage of urine or the passage of the causeof the obstruction, such as kidney stones. The ureteral stent functionsby dilating the ureter to allow urine to flow and may also act as aguide for urine within the ureter, using the holes located along thelength of the catheter or stent.

Although stenting is an effective technique for aiding in the passage ofboth urine and stones, the presence of the device in the ureter cancause complications. According to Kunin, 40% of all hospital-associated(nosocomial) infections are related to the urinary tract (Kunin, 1987).Of these urinary tract infections, 80% are a consequence ofcatheterization (Fowler, 1989). After only one week of indwellingcatheterization, the risk of infection is about 50%. Suchcatheterization is used in about 20% of patients in chronic carefacilities such as nursing homes. More than 50% of these patientsexperience encrustation and blockage of their catheters, which inhibitsthe flow of urine. Inhibited flow can lead to a host of more seriousproblems for the patient if not corrected.

There are at least three possible mechanisms by which a catheterizedureteral area becomes infected. Bacteria can be introduced during theinsertion of the stent, or the organisms can enter the urinary tractthrough the urethral meatus and subsequently migrate along the stent.The third possibility is that the bacteria utilize their ability to risewithin a volume of fluid. The bacteria can actually migrate up theurinary tract via the urine (Franco et al., 1990). Once the bacteriahave been introduced and colonize an area it takes only 24-48 hours fora relatively low concentration of bacteria (10² -10⁴ /ml) to grow into aclinically significant population (≧10⁵ /ml) (Stamm, 1991).

Once established, the bacteria migrate along the catheter aided by theformation of biofirms (Nickel et al., 1992). Biofilms are aggregationsof microorganisms surrounded by an extracellular matrix ofexopolysaccharide (Swartz et al., 1991). The bacteria are sandwichedbetween this polysaccharide coat and the catheter. Therefore, thebacteria are isolated and separated from the surrounding ureteralenvironment. This isolation can lead to complications in executing aneffective therapy against the bacteria due to their protection withinthe biofilm (McLean et al., 1991).

Certain species of bacteria such as the Gram-negative microbe Proteusmirabilis secrete the enzyme urease that degrades urea in the urine toform carbon dioxide and ammonia. The presence of ammonia increases thepH of the urine leading to the precipitation of magnesium ammoniumphosphate salts and certain calcium phosphate salts. Struvite,hydroxyapatite, and carbonate apatite account for 10-20% of urinaryencrustations (Olson et al., 1989). Although this fraction is small, thepresence of these encrustations is considered a more significant risk tohealth than the presence of other stones because of their high growthrates.

Catheters dipped and coated in antibiotic solutions have been producedto address the problem of infections developing with ureteralcatheterization. See, for example, Izumi et al., EP 0 065 884;whitbourne et al., EP 0 426 486; and Soloman, U.S. Pat. No. 4,999,210.Prophylactic use of antibiotics to control the bacteria that cause theseencrustations, however, has proved unsatisfactory. Despite use ofantibiotics, such as ciprofloxacin, given systemically, bacteria growand multiply within the biofilm slime layer on urinary catheters.Continuous use or release (Reid et al., 1993; Soloman and Shevertz,1987) of antibiotics in the absence of infection is of debatable meritbecause of drug side effects and the possibility of producing resistantstrains.

Prevention of encrustation can be achieved by using a urease inhibitorto prevent the degradation of urea. The urease inhibitor competes withurea for active sites on the urease molecule. Various chemicals havebeen studied for their effect on the activity of urease and thecrystallization of struvite (ammonium magnesium phosphate). Chondroitinsulfate and heparin sulfate have proven ineffective in preventingstruvite encrustation. Sodium citrate shows potential; however, themechanism of control does not involve the actual inhibition of ureasebut involves a possible complexation of the Mg⁺⁺ ions (McLean et al.,1990). Silver is used as a surface modification for preventing catheterbacteriuria (Liedberg et al., 1990).

Acetohydroxamic acid (AHA) is another option for prevention ofurease-associated encrustation. It inhibits urease in a manner similarto boric acid (Breitenbach and Hausinger, 1988). Acetohydroxamic acidhas been shown to be rapidly metabolized with a half-life ofapproximately five to ten hours (Takeuchi et al., 1980).

In selecting a stent or catheter, certain characteristics are desirable.The material should not prompt an immune response. The tube should alsobe flexible enough to avoid discomfort to the patient duringcatheterization but stiff enough to allow easy insertion. The polymercomposing the stent should be sterilizable and should maintain itsmechanical properties throughout the duration of implantation (Brazziniet al., 1987; Mardis, 1987). Common ureteral stent materials include:C-FLEX (styrene-ethylene/butylene block copolymer modified withpolysiloxane); polyurethane; silicone; and SILITEK.

Hydrogels are polymers which absorb water and swell in aqueousenvironments. Hydrogels are usually polymerized from a hydrophilicwater-soluble monomer such as acrylic acid and crosslinked to yield anetwork polymer. When water is absorbed, the crosslinks prevent thepolymer from dissolving, and the polymer swells (Tarcha, 1991).

Hydrogels have been used for many medical applications including contactlenses and surgical drainage tubes (Lee, 1988; Pearce et al., 1984).Hydrogels have also been used for coating urinary catheters or haveactually been formed in the shape of a tube for use as a catheter(Ramsay et al., 1986). Upon swelling, the hydrogel's coefficient offriction is reduced, and the polymer becomes slippery. This propertymakes insertion and removal of the catheter less traumatic and reducesthe inflammatory response of the urothelial tissue. Controlled releaseof active agents, such as antibiotics, from hydrogels is anotherapplication that is advancing rapidly (Soloman and Sheretz, 1987).

BRIEF SUMMARY OF THE INVENTION

The subject invention concerns a method for the controlled release of anagent from a pH sensitive polymer. The agent is released from the matrixof a polymer gel when the pH of the surrounding environment reaches adesired level. This method of controlled release can be used to ensurethat the agent is delivered to a specific area and delivered only whenthe need for the agent arises. Methods such as these are also sometimescalled stimulated, regulated, or triggered release.

A polymer gel comprising hydrophobic, weakly acidic and neutralcomonomers will swell more in a basic environment than in a neutral oracidic environment due to formation of a hydrophilic polyelectrolyte andmay be used to effect the controlled release of a biologically activeagent. In a preferred embodiment, elastomeric polymers comprisingbutylmethylacrylate and methacrylic acid may be used according to thesubject invention. Further, a hydrogel polymer comprising the comonomersmethyl methacrylate and acrylic acid can be used according to thesubject invention. The swelling behavior of this polymer was measuredand determined to be pH sensitive due to the presence of the acrylicacid moieties. In this embodiment, the greatest swelling occurs at a pHvalue of 9.0.

Specifically, a copolymer hydrogel made of 90% methyl methacrylate and10% acrylic acid was synthesized. The crosslinking agentdiethyleneglycol dimethacrylate and the initiator2,2'-azobisisobutyronitrile (AIBN) were used. Acrylic acid and methylmethacrylate were purified by distillation before use. The acrylic acidgroups throughout the polymer chains ionize in a basic environment, andswelling subsequently occurs. A biologically active agent trapped withinthe polymer matrix is released into the environment upon swelling of thematrix.

In a specific embodiment of the subject invention, the exemplifiedhydrogel polymer is coated onto a surface. Upon swelling in an alkalineenvironment, this hydrogel releases a preloaded therapeutic agent forpreventing or reducing the production and precipitation of magnesiumammonium phosphate hexahydrate (struvite). In a preferred embodiment,the agent of choice is acetohydroxamic acid (AHA), a known ureaseinhibitor. This drug competes with urea for the active sites on urease,an enzyme secreted by many bacteria, such as Proteus mirabilis, whichinfect the urinary tract. This competitive inhibition prevents theproduction of ammonia, which is the impetus for struvite precipitation.

The drug release profile of the exemplified hydrogel polymer used in theclaimed controlled release method was observed and recorded. Wediscovered that acetohydroxamic acid experiences zero-order release fromthe polymer matrix with both diffusional and swelling control. The agentis released at the greatest rate and magnitude at pH 9.0.

The activity of acetohydroxamic acid in inhibiting urease was measured.It was determined that the inhibitor functioned to reduce the pHincrease of urine at concentrations released by the hydrogel. Thus, theacetohydroxamic acid release system of the subject invention can be usedin therapy for the prevention of urease-induced ureteral catheterencrustation.

To adjust the flexibility of the coating, various combinations ofmonomer can be used, or the active composition (pH sensitive polymerplus antibiotic) can be formed into microspheres and incorporated intoan elastomeric matrix in the same way that a filler, such as SiO₂, iscurrently used in an elastomer such as silicone.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the structure of the methyl methacrylate/acrylic acidcopolymer hydrogel exemplified by the subject invention.

FIG. 2 shows the swelling behavior of the methyl methacrylate/acrylicacid copolymer hydrogel at various pH values.

FIG. 3 shows the release rate of acetohydroxamic acid from the methylmethacrylate/acrylic acid matrix as a function of pH.

FIG. 4 shows the cumulative release of acetohydroxamic acid from themethyl methacrylate/acrylic acid hydrogel.

FIG. 5 shows the percent release of acetohydroxamic acid from the methylmethacrylate/acrylic acid hydrogel as a function of pH.

FIG. 6 shows the effect of acetohydroxamic acid on the activity ofurease.

DETAILED DISCLOSURE OF THE INVENTION

One embodiment of the subject invention involves a coating for naturalrubber (latex) catheters which releases an antibiotic or otherbiologically active agent only when the environment becomes basic oracidic. For example, the agent may be released above a pH of about 8.5.The coated catheter can be used to reduce encrustation associated withstruvite production, which is due to ammonia formation inbacteria-infected urine. The coated catheter with the on-demand releasesystem further avoids problems associated with continuous slow releasesystems.

Release of an antibiotic when bacterial surface growth is present, butnot at other times, advantageously controls bacterial growth without theexcessive release of antibiotics. A specific embodiment of the subjectinvention concerns a pH responsive polymer or hydrogel which is usefulfor the pH stimulated release of an antibiotic into infected urine.Bacterial presence is detected by sensing a pH change induced by theurease-producing organism which causes the release of basic ammonia intothe urine. High pH causes minerals in the urine to precipitate, formingencrustations. A pH-sensitive polymer such as a weak carboxylic acid canbe used so that when the pH increases, ionization occurs and the polymerbecomes swollen, causing antibiotic to be released which kills theurease-producing bacteria. Control of these bacteria helps regulateurine pH.

A second novel approach to the inhibition of stent encrustation isdirected toward the control of the formation of the encrustation. Ureaseenzyme produced by the infecting bacteria is believed to be a primaryfactor resulting in the precipitation of magnesium in the urinary tract.Competitive inhibition of urease may be achieved through the use ofacetohydroxamic acid (AHA), a stable synthetic compound derived fromhydroxylamine and ethyl acetate. Its molecular structure resembles urea.Acetohydroxamic acid (AHA) has a molecular weight of 75.07 g/mole and amelting point range of 89°-91° C. The pKa of AHA is 9.3. The mechanismof inhibition is the competitive binding of the amic acid group to theurease (Wu et al., 1985). As the acid binds to the enzyme, the number ofavailable active sites for the binding of urea decreases, and less ureais degraded. The pH of the urine, therefore, does not become asalkaline. The effectiveness of this agent has been shown in otherstudies (Soriano et al., 1987; Griffith et al., 1988). The release ofacetohydroxamic acid can be measured using UV/VIS spectrophotometry. Thedrug reacts with FeCl₃ to form a colored complex that absorbs light at515 nm.

Despite being well absorbed from the gastrointestinal tract, AHA use ispotentially limited by the development of Coomb's hemolytic anemia, GIcomplaints, bone marrow depression, and teratogenicity in patients(Griffith et al., 1991). The local release of AHA by the methods of thesubject invention can be used to increase concentrations of theunmetabolized drug administered to a patient while reducing the drug'spotential side effects. AHA can be bound to catheter material by ahydrophobic/unionized polymer such as styrene/p-hydroxy styrenecopolymer. These polymers swell in a pH greater than about 8.5,resulting in the controlled release of AHA only in the presence ofincreased urine pH (indicative of a urease-producing bacterialinfection). Other useful polymers include substituted acrylates and alsop-hydroxystyrene polymers and copolymers.

A polymer having a high glass transition temperature (105° C.) may besuitable to coat the body of the catheter; however, it is not possibleto coat the expanding balloon at the tip of the catheter with thismaterial. Simply coating the body of the catheter may be sufficient;however, the method more generally applicable to commercial use is asimple dip coating of the whole catheter. Therefore, the subjectinvention includes the use of not only glassy polymers but alsoelastomeric polymers capable of releasing an agent in a basicenvironment.

Two types of changes can be exploited in preparing polymers andmaterials to be used according to the subject invention. These changesadjust the release rate of the agent. The copolymer composition can beadjusted so that the agent being released is less soluble or less mobilewithin the gel layer. Permeability (P) is equal to the mobility andconcentration within a matrix and is usually expressed as the diffusioncoefficient (D) times the solubility in that matrix (S), i.e., P=D·S.All elastomers have a higher free volume (greater than 2.5%) than othermaterials that have glass transition temperatures below their own, suchas polystyrene. Hence, it is likely that the mobility part ofpermeability would be greater in cases where elastomers are employedinstead of glassy systems.

Hence, the solubility portion of the relationship must be adjusted todecrease the overall permeability. There are a number of elastomericcompositions that may be used according to the subject invention thathave a sharply different solubility parameter than many of the commonlyused therapeutic agents. For instance, fluoro elastomers are availableby polymerizing fluoro-substituted alkylmethacrylates with methacrylicacid. In addition, simply using monomers with long hydrocarbon chains, avery low solubility will occur for water soluble agents such as AHA. Thecopolymer composition also allows one to make shifts in the transitionof pH-sensitive swelling to either a higher or lower pH value.

The other broad type of change that can be made to adjust agent releaserate is to adjust the molecular weight of the diffusing therapeuticagent by selecting a different agent. There is a variety of broadspectrum antimicrobials which can be used to kill all bacteria presentwhen released from the gel. These range from very low molecular sizemolecules such as silver ion (silver incorporated in a soluble form) tointermediate molecular weight species such as chlorohexidine, and,finally, to larger antimicrobials such as gentamicin. The larger themolecular size, the lower the diffusion rate will be through the matrix,given comparable solubility. Those skilled in the art can select andutilize many combinations of coatings and agents that can be adjusted torelease at a basic pH.

The on-demand controlled release method of the subject invention isparticularly advantageous because the antibiotic is only released attimes when contaminating bacteria are present. Antibiotic is notcontinually released. There are at least three important advantages ofthis action: (1) tissue damage is restricted significantly compared toeither continuous release or high level bolus instillation, (2)drug-resistant bacteria are not selected for growth since there are muchlower levels of antibiotic present, and (3) fewer side effects due tosystemic absorption occur because total levels of antibiotic needed arelower.

Another advantage of this delivery method is that devices comprising thehydrogel polymer do not need to be antibiotic-loaded at the time ofsale; instead, they may be loaded by solvent or pH-induced swellingbefore use by the personnel inserting the device.

It should also be noted that this system does not prevent applying anadditional hydrogel layer as the outermost layer on a catheter. Theinnermost layer of the Foley catheter can be a standard elastomer formechanical properties. A second layer can be the pH sensitive releasinglayer. The final layer can be a hydrophilic coating such as is currentlyused on many catheters. Additionally, microspheres made of the polymercompositions of the subject invention can be incorporated into one ofthe layers. Such microspheres need to swell only a very small amount tobegin release and once again give a pH release profile from an otherwisemechanically or lubricity functioning polymer layer.

Although specific embodiments of the subject invention are providedherein, it would be apparent to one skilled in the art that thecontrolled release method of the subject invention is useful for anumber of applications. Specifically, the controlled release polymers ofthe subject invention can be used for other types of indwelling devices,such as heart valves, pacemakers, artificial joints, intravenous orintraarterial catheters or devices that are inserted into the bodycavity such as gastrointestinal tubes, intrauterine devices, ordiaphragms. The polymer matrix utilized within these devices can betriggered to release biologically active agents when the pH of theenvironment turns either acidic or basic. This change in pH may be dueto changes occurring naturally in the environment or changes induced byan operator. For example, at a desired time, the operator may release abasic reagent into the environment of the polymer to effect the desiredrelease of the agent entrapped in the polymer matrix.

Urinary catheters, including Foley catheters and catheters that have noballoon, and ureteral stents, may be used according to this disclosureto prevent urease activity or prevent bacterial infestation. Allindwelling stents, shunts or tubes are likewise susceptible to coatingwith an elastomeric polymer containing antibiotic or other activeagents, including dyes or sterilants (chlorine dioxide, phenolics,acetic acid, alcohols, ethylene oxide, H₂ O₂) which are released uponswelling of the elastomer.

Furthermore, gastrointestinal tubes may be likewise treated with anelastomeric coating. In this event, for example, upon excessiveproduction of acid, an agent such as an anti-acidic compound, or an H₂acid release blocker such as famotidine, ranitidine, omeprazole, andlike compounds, including their hydrochloride or other salts, could bereleased from an acid-expansive elastomer to prevent further release ofacid. These principles could also be applied to gastrointestinal feedingtubes that must remain in place for prolonged periods and which, in theabsence of antibiotic or other active agent release, may become a nidusfor bacterial infection or ulceration. In this respect, release of anagent such as a urease inhibitor or antimicrobial which is particularlyadapted to combat Heliobacter pylori, associated with peptic ulcers, ismost beneficial.

The polymer or hydrogel may be modified to effect release in acidicenvironments by inclusion of weakly basic comonomers, which swell morein an acidic environment than in a neutral or basic environment.

The foregoing principles are likewise applicable to the provision oftubing used in respiratory therapy, including, but not limited to watertrap lines and ventilation tubes.

Where the agent released is a dye, acid or alkali production at the siteof a sutured wound, indicating onset of infection, could be easilyidentified if a dye were released from elastomer coated sutures whichrelease the dye upon expansion in the acidic or alkaline environment.Furthermore, the sutures may be coated with an elastomer which releasesan antibiotic or any other agent desired.

In yet another application of the principles of this invention, activeagents may be released from contact lenses either prepared with aparticular elastomer, coated with the elastomer or simply ringedtherewith around the circumference of the lens. In this way, should anyeye infection develop, or a nidus of bacterial growth within the lensdevelop, antibiotic or other agents, are released upon buildup ofbacterial metabolites which alter the ocular pH.

In a further application, the devices and methods of this invention maybe applied to penile implants, heart pacemakers and neural shunts (forrelieving fluid pressure from the brain), each of which may be improvedby incorporation therein of an active agent according to this invention,which releases an active agent upon exposure of the device to apre-determined high or low pH.

Additionally, the claimed method is applicable to a variety ofnon-health care uses, including industrial settings in which it isdesirable to have an agent released at a certain pH. Such uses caninclude all types of surfaces including, but not limited to, pipes, foodproduction equipment, or chemical vats. The controlled release polymercan be incorporated into cat litter or other pet products which willrelease an antibiotic, deodorant, or dye upon a change of pH associatedwith urine, as well as fabrics and diaper materials.

In another industrial application of this invention, the pH sensitivepolymer matrix of this invention is used as a food-wrap, such that ifthe food, for example meat, becomes contaminated by bacterial infection,the wrap will release a dye or other indicator as the pH increases ordecreases beyond a pre-set limit. In this way, spoiled food will not beconsumed. In addition, a dye could be released from microspheres,intermixed with food, e.g. ground meat. The dye releasing polymer may bean interpenetrating network or a coating.

In another application, for example where the walls of a clean room,spacecraft, or space station must be free of bacterial contamination,the walls may be coated with the pH sensitive polymer matrix and anindicator or sterilant released should bacterial contamination of thewalls occur. Likewise, sterilants or pH buffers could be released fromthe walls or bottom of a swimming pool or from a free floating containeras the pH drops or rises beyond a pre-determined limit.

One aspect of the subject invention concerns the use of an oxidationtechnique followed by solution grafting of polyacrylamide onto a naturalrubber latex substrate in order to produce a hydrogel coating which isvery slippery and can also function as a pH-stimulatedcontrolled-release device which releases an active agent under basicconditions. In this embodiment, the coating is adherent to the substrateand is flexible and elastic. One particular oxidizing system that can beemployed according to this aspect of the subject invention utilizesformic acid and hydrogen peroxide. The grafting of acrylamide ontooxidized polymer substrates can use ceric ion initiation using naturalrubber as a substrate. Other types of substrates normally used forcatheters can also be modified by this technique. These would includeplastic, elastomeric polymers, including but not limited to polyolefincopolymers, silicone, polyurethanes, and polyesters, for example.

A further aspect of the subject invention concerns the use of aninterpenetrating network of pH-sensitive copolymer and natural rubber.This technique involves swelling the rubber with a solution offree-radical initiator in monomer, and then effecting polymerization inorder to produce an interpenetrating network. In order to incorporateenough monomer into the substrate, it is preferable for one of themonomers to be hydrophobic so that it is most compatible with therubber. Also, one monomer is preferably capable of becoming hydrophilicwhen the pH is raised or lowered. Furthermore, the resulting polymerneeds to be in situ-crosslinkable in order to ensure stability. Thisadvantageous system can be achieved by using a blend of a difunctionalhydrophobic monomer with a hydrophilic monomer. Specifically, excellentresults can be achieved with a monomer which is a C14∝C16 dioldimethacrylate (produced by Sartomer Company, #SR2100). This can becombined with acrylic acid as the hydrophilic monomer in a ratio ofabout 5 to about 30% acrylic acid. Other possibilities for thehydrophobic monomer include, but are not limited to, mono-, di-, andtri-functional acrylates and methacrylates with various alkyl chainlengths from approximately 4 to 25. Other hydrophilic monomers wouldinclude, but are not limited to, methacrylic acid or p-hydroxy styrene.This process is enhanced by first oxidizing the rubber samples. Thisprocess can also be used with a variety of catheter materials asdescribed above. The material produced by this method is flexible andelastic, and because it is a network rather than a coating, it does notpeel off or debond. This technique has been used to prepare apH-sensitive controlled-release device capable of releasing a desiredcompound when the pH rises above approximately 8.

Materials and Methods

Polymer synthesis. A modified suspension polymerization method (Batichet al., 1993) can be utilized. Monomers are freed from the inhibitor bywashing with aqueous NaOH or by distillation. Solubility of a weak acidmonomer (p-hydroxystyrene or methacrylic acid) can be reduced by workingin acid aqueous solutions with NaCl added as needed to salt out themonomer. In a high speed stirrer (c. 300 rpm) equipped 500 ml flaskunder nitrogen, 200 ml of pH 3 buffer (with NaCl as needed) areintroduced and stirring is commenced. A suspension stabilizer such aspolyvinyl alcohol can be added as needed (about 0.5 g). A well mixedsolution of monomers (20 ml) containing 0.2 g AIBN is added and stirringcontinued while heating to 70° C. for four hours, then 80° C. for threehours. The reaction products can be filtered and washed with pH 7.0buffered methanol and then dried. Modifications in the initiator,stabilizer, and reaction conditions used can be made by those skilled inthe art utilizing the subject disclosure. Polymer can be purified bydissolving in an organic solvent such as tetrahydrofuron (THF) oracetone and precipitating in water. For microsphere synthesis, a similarmethod is used except divinylbenzene cross-linking agent is added to themonomer mix to make a 1% solution of organic components (i.e., 0.2 g inthe 20 g).

To simplify expected polymer compositions, styrenics can be reacted withthemselves, and acrylates with themselves, although styrenics can alsobe reacted with acrylates. The monomer p-octylstyrene can be used withp-hydroxystyrene and styrene. A separate series of reactions can be doneusing methacrylic acid and n-alkyl acrylates. Poly-n-octylacrylate has abrittle point of -60° C. (Saunders, 1988) and should be elastomeric andhydrophobic enough to provide reasonable release profiles.

Linear polymers can be prepared by solution methods in organic solvents.The suspension products provide a geometry easy to use for swellingstudies. Butyl and hexyl acrylates, as well as decylmethacrylate, formsoft polymers at room temperatures and are usable hydrophobic monomers.These monomers are commercially available from several sources (e.g.,Aldrich, or Dajac Laboratories). Extreme hydrophobicity can be achievedby using perfluoroacrylates, such as tetrahydroperfluorodecylmethacrylate.

Measurement of swelling. For small drug molecules, only a few percentswelling of the matrix is necessary to allow release. For release ofgentamicin or other larger drug molecules, greater swelling is needed.Swelling can be controlled by cross-link density.

For suspension polymerized glassy polymers, equilibrium is achievedwithin about two days (usually within one day), although swellingcommences much more quickly. Elastomers will swell faster.

About 0.4 g of microsphere beads are immersed in 100 ml buffer at 25° C.for two days with the buffer being replaced several times to reach aconstant pH on the first day. The water content can be determined by thecentrifugation method described by Pepper (Pepper et al., 1952) whereswollen beads are transferred to a filter tube and centrifuged to removemost of the water. The tube is then weighed and dried in a vacuum ovenat 70° C. to a constant weight. The change in weight represents absorbedwater and is reproducible to less than 2% when water contents are 75%.

Citrate buffers can be used and adjusted to an ionic strength of 0.3Mwith NaCl. An Orion pH meter is used to monitor pH values.

Drug loading. Comonomers having greater hydrophobicity tend to swell toa larger extent in an organic solvent such as THF or ethanol than inwater. Hence, the copolymers can be loaded with the agent by swellingthe microspheres or film coatings in ethanol containing a highconcentration of an alcohol soluble drug. Gentamicin, chlorhexidine, andhippuric acid are all highly soluble in alcohols. Ethanolic solutionscontaining from about 15% to about 30% drug are heated to 50° C. and thepolymer placed in them for about 1 hour. Upon removal, the polymer isplaced in a vacuum oven at 50° C. for several hours (until constantweight). The polymer is then be washed with neutral water to removesurface deposits of drug. The amount of drug incorporated can bedetermined by extraction with dilute aqueous sodium hydroxide (morebasic than pH=10.0) and measurement of the released drug byspectrophotometry.

Very low concentrations of gentamicin are normally used in plasma (lessthan 2 mcg/ml) because of systemic nephrotoxicity. For slow release,levels will be highest at the surface of the catheter where the bacteriagrow. Gentamicin has been shown to be highly effective against Proteussp. and other urease-producing organisms. Because the volume of liquidadjacent to a catheter is small and the removal rate for this layer islow (there is no urine or blood flow at this interface), release ratesof about 0.1 mcg/min for a one-inch segment of catheter can be used.Hence, at least about 1.4 mg of gentamicin can be loaded in eachone-inch segment of catheter.

Measurement of drug release. One-inch segments of coated Foley cathetersmay be placed in 100 ml of 37° C. buffer at pH 7.4 and also 9.0. A 5 mlaliquot of the buffer solution is removed at 4 hours, 8 hours, and 24hours for analysis by UV-spectrophotometry or HPLC. The 5 ml will bereplaced with fresh buffer each time. The exact drug being released isless important than demonstrating the mechanism of stimulated release.Therefore, other easily observed agents such as fluorescein ortetracycline which absorb light in the visible range and have largerextinction coefficients than gentamicin may be used to test drugrelease. If difficulties arise with simple spectrophotometric detectionat low levels, concentration by evaporation, or switching to an HPLCmethod can be used.

Following are examples which illustrate procedures, including the bestmode, for practicing the invention. These examples should not beconstrued as limiting. All percentages are by weight and all solventmixture proportions are by volume unless otherwise noted.

EXAMPLE 1 Methyl Methacrylate Acrylic Acid Hydrogel Synthesis

Various polymer compositions were synthesized. Table 1 shows theparameters that were varied. The monomers used were acrylic acid (AA)and methyl methacrylate (MMA). If the percent of monomer was less than100, then the cosolvent was distilled water. Crosslinking agents usedwere diallylamine (DA), which is pH sensitive; tetraethyleneglycoldimethacrylate (TEGMA); diethyleneglycol dimethacrylate (DEGMA); andethyleneglycol dimethacrylate (EGMA). The initiators were ammoniumpersulfate for the aqueous polymerizations and2,2'-azobisisobutyronitrile (AIBN) for the organic polymerizations. Itwas determined by visual inspection of the swelling properties in waterthat, of the different polymer compositions listed here, the MMA/AA(90/9) polymer displayed the least solvent absorption.

                  TABLE 1                                                         ______________________________________                                        Experimental parameters for polymer synthesis                                                                        reaction                                                    crosslinker       time                                   monomer (%)                                                                              % monomer (%)       initiator (%)                                                                         (hr)                                   ______________________________________                                        AA (100)   60        DA (2)    AP (0.5)                                                                              4                                      AA (100)   40        DA (2)    AP (0.5)                                                                              4                                      AA (100)   20        DA (2)    AP (0.5)                                                                              4                                      AA (100)   40        DA (5)    AP (0.5)                                                                              4                                      AA (100)   60        DA (10)   AP (0.5)                                                                              4                                      AA (100)   60        DA (15)   AP (0.5)                                                                              4                                      AA (100)   60        DA (20)   AP (0.5)                                                                              4                                      AA (100)   60        TEGMA (5) AP (0.5)                                                                              4                                      AA (100)   60        DEGMA (5) AP (0.5)                                                                              4                                      AA (100)   60        EGMA (5)  AP (0.5)                                                                              4                                      MMA/AA (99/10)                                                                           100       DEGMA (1) AIBN (0.5)                                                                            24                                     MMA/AA (85/15)                                                                           100       DEGMA (1) AIBN (0.5)                                                                            24                                     MMA/AA (80/20)                                                                           100       DEGMA (1) AIBN (0.5)                                                                            24                                     MMA/AA (70/30)                                                                           100       DEGMA (1) AIBN (0.5)                                                                            24                                     MMA/AA (60/40)                                                                           100       DEGMA (1) AIBN (0.5)                                                                            24                                     MMA/AA (90/9)                                                                            100       DEGMA (1) AIBN (0.5)                                                                            24                                     ______________________________________                                         See text for definitions of abbreviations.                               

Two equally sized glass plates were clamped together separated by asilicone tube. The tubing was manipulated into the shape of a "U" withthe ends extending beyond the edge of the glass, forming a well or moldfor placing the monomer solution. The inner surfaces of the mold werecoated with Sigmacote, a silicone solution used to prevent the glassplates from sticking to the polymer gels. Acrylic acid (Sigma, St.Louis, Mo.) was distilled at 56° C. and 20 mmHg. Methyl methacrylate(Sigma) was distilled at 58° C. and 160 mmHg. Table 2 lists thereactants and amounts that were used for the polymerization.

                  TABLE 2                                                         ______________________________________                                        Reactants for hydrogel synthesis                                              Reactant        Amount (g)                                                    ______________________________________                                        acrylic acid    9                                                             methyl methacrylate                                                                           0.9                                                           DEGMA           0.1                                                           AIBN            0                                                             ______________________________________                                    

The two monomers were mixed, and the initiator and crosslinking agentwere mixed in separate containers. These two mixtures were then mixedtogether with a stir bar for approximately 10 minutes. Forpolymerizations in which water was a cosolvent, degassing with argon wasdone to remove O₂ radical scavengers. The monomer solution was thenplaced into the glass molds by loading it into a syringe and thendispensing the solution into the mold. The molds were placed into a 60°C. oven for 24 hours. After polymerization, the gels were soaked in a 90v/v % ethanol solution at 37° C. for approximately 48 hours, withchanging of the solvent after 24 hours. The ratio of extraction mediumto polymer was approximately ten to one. This soaking was done to removeany residual monomer or oligomers present in the polymer. At 24 hours,the characteristic odor of methyl methacrylate could be detected in theethanol solution. The odor was absent at 48 hours. The gels were cutinto square shaped pieces and dried under vacuum at 60° C.Polymerization of the hydrogel with the AHA dissolved in the monomer wasattempted, but the reaction did not occur, probably due to blocking ofthe radicals necessary for this type of polymerization.

FIG. 1 shows the structure of the copolymer synthesized that wassubsequently used for drug release assays. The crosslinker is shown inthe center. The lines extending from either end of the dimethacrylatemolecule represent the polymer chains composed of methyl methacrylateand acrylic acid. The exact values of "x" and "y" in the structure areunknown; however, an estimate can be calculated using the reactivityratios of the monomers. The reactivity ratio for methyl methacrylate(r₁) is 2.150 for a copolymerization with methyl acrylate, the methylester of acrylic acid. Methyl acrylate has a reactivity ratio (r₂) of0.400 (Greenley, 1989). Therefore, both monomers preferentially addmethyl methacrylate. The mole fraction of methyl methacrylate in thecopolymer (F₁) can be calculated from equation one (Odian, 1981).##EQU1## The mole fraction of each monomer before polymerization isgiven by f₁ for methyl methacrylate and f₂ for the comonomer. Thecalculated value of F₁ is 0.95, which means that the bulk of the polymerwill be composed of methyl methacrylate, yielding a predominantlyhydrophobic polymer.

EXAMPLE 2 Hydrogel Swelling Study

The swelling behavior of the synthesized hydrogel was observed at pHvalues of 4.0, 5.0, 7.4, and 9.0. All buffers were purchased from FisherScientific (Pittsburgh, Pa.). The pH 7.4 buffer contained 0.05Mpotassium phosphate monobasic and sodium hydroxide, and the pH 9.0buffer contained 0.1M boric acid, potassium chloride, and sodiumhydroxide. The pH 4.0 buffer contained a mold inhibitor thatparticipated in a side reaction with the AHA detection solution. Acitric acid buffer composed of citric acid and trisodium citrateadjusted to pH 4.0 was substituted. The buffer at pH 7.4 also reactedwith the detection solution but not to the extent that the buffer at pH4.0 did. The precipitate was filtered with a 2.0 μm syringe filter. Sixdried hydrogel pieces were separated out for each pH being tested. Eachindividual piece was weighed and placed into a separate labeled testtube. Into each test tube 4 ml of buffer solution were pipetted. Thetest tubes containing both the polymer samples and the buffer wereplaced into a 37° C. water bath. Samples were removed from the testtubes at 24, 48, 72, 96, 120, 144, and 168 hours. The samples wereblotted with a tissue in order to remove any excess buffer on thesurface. After blotting, the samples were weighed and placed into thebuffer again for further swelling until an equilibrium weight wasreached. The swelling ratios of the gels were calculated for each timeinterval using equation one.

During the swelling study, the dimensional change that occurred in thehydrogel was unnoticeable. This small dimensional change is in contrastto the high swelling exhibited by the pure acrylic acid hydrogelssynthesized by Park (Park, 1988). The differences in swelling can beattributed to the high concentration of hydrophobic methyl methacrylatein the polymer. The methyl methacrylate regions of the polymer form abarrier to aqueous solutions and hinder movement of the solvent frontinto the matrix. Therefore, the equilibrium volume of solvent thatpermeates the matrix is decreased.

FIG. 2 shows the swelling behavior of the MMA/AA hydrogel at fourdifferent pH values. As the pH of the swelling medium increases, thereis a small increase in the swell ratio until the pH reaches 9.0. At thisvalue, the polymer exhibits a marked increase in the swell ratio due toincreased ionization of the acrylic acid. This increase at pH 9.0 is thedesired effect for AHA release as the urease activity increases the pHto approximately 9.0 if allowed to proceed without therapy. The MMA/AAcopolymer with an AA content of 9% exhibits behavior that disagrees withthe observation of Bronstedt that, with 10% AA content, little pHsensitivity is seen in the polymer (Bronstedt and Kopecek, 1991). Thesamples in the pH 4.0, 5.0, and 7.4 buffers reached an equilibriumsolvent content at approximately 48 hours while the samples in the pH9.0 buffer did not reach equilibrium until approximately 144 hours. Themaximum swell ratio reached at pH 9.0 was 0.16 compared to a minimumswell ratio at pH 4.0 of approximately 1.7 in a swelling study ofpoly(hydroxyethylmethacrylate) (HEMA) (Brannon-Peppas and Peppas, 1990).

One possible mechanism for the relatively high swelling observed at pH9.0 is the hydrolysis of the MMA pendent groups to carboxylate groupswhich can then ionize and further increase the swelling (DeMoor et al.,1991). If degradation of the methyl methacrylate to acrylic acidoccurred, it would be accompanied by a mass loss of the polymer. DeMoorfound, however, that the swelling was slower at higher pH values butthat the final equilibrium swell ratio was higher. The MMA/AA data donot agree with DeMoor's findings as the polymer swells faster andgreater at pH 9.0. Eckstein et al. observed large volume changes betweenpH values of 6.0 and 7.0 in the HEMA hydrogel they studied forprevention of encrustation (Eckstein et al., 1983). This pH range is tooacidic for the desired application of urease inhibitor release. If largeswelling occurs before a significantly alkaline environment is produced,the AHA will diffuse out rapidly and be diluted and washed away by theflow of urine through the ureter (60 ml/hr), leaving nothing to inhibitthe activity of the urease. The swelling properties of the hydrogel ofthe subject invention were not measured after loading the polymer withthe AHA, but it is suggested that the presence of a drug in the polymerincreases the swelling (Robert et al., 1987). The release of the drugwas therefore studied as a function of pH. The release will depend onthe pH related solubility of the drug as well.

EXAMPLE 3 Hydrogel Drug Release Study

Six pieces of the MMA/AA (90/9) polymer were weighed in the dry state.Each piece was placed into 4 ml of a separate solvent. The solvents usedwere pH buffers with pH values of 4.0, 7.4, and 9.0, 90 v/v % ethanol,methanol, and 90 v/v % acetone at 37° C. This experiment was conductedto determine which solvent resulted in the most swelling of the gel fordrug loading purposes, since the AHA is very soluble in all the chosensolutions. The results indicated that the 90% acetone solution elicitedthe largest swelling ratio. A 16 w/w % solution of acetohydroxamic acidin 90% acetone was prepared. This concentration was near the saturationpoint as more acetohydroxamic acid could not be dissolved in thesolvent.

The drug release profile of the synthesized hydrogel was characterizedat pH values of 4.0, 7.4, and 9.0. Hydrogel pieces were weighed in thedry state. Six pieces weighing approximately the same were separated outfor each respective pH buffer value. Each gel piece was individuallyplaced into a test tube containing 3 ml of the 16% AHA acetone solution.The test tubes were capped and wrapped in parafilm to preventevaporation of the solvent. The test tubes were placed into a 37° C.water bath for 48 hours. The hydrogel pieces were then removed from theAHA solution and placed in a vacuum oven at 60° C. for solventevaporation and then at room temperature for a total drying time of 72hours. The drug-loaded gels were then reweighed, and the total AHAcontent was calculated.

For each drug-loaded hydrogel piece, a series of eight test tubescontaining 4 ml of buffer solution was prepared. Each gel piece wasplaced into the first test tube labeled "1 hr" and remained there for 1full hour at 37° C. At 1 hour, each piece was transferred from the firsttest tube to the second test tube labeled "2 hr." This procedure wasrepeated at 6 and 24 hours. Samples were dried, and the release wasinitiated again and measured at 24, 51, 72, and 105 hours. All solutionswere then mixed with a Vortex mixer.

Standard solutions of AHA were prepared at concentrations of 750, 375,187.5, 75, and 7.5 μg/ml by adding 0.075 g of AHA to a 100 ml volumetricflask and filling to volume with buffer. Serial dilutions of theseconcentrations were then performed. These standard solutions wereprepared at pH values of 4.0, 7.4, and 9.0. A 0.1M solution of FeCl₃ wasprepared by adding 13.516 g of FeCl₃ to a 500 ml volumetric flask andfilling to volume with distilled water.

Three milliliters of the FeCl₃ were pipetted into a series of test tubescorresponding to test tubes in which the drug release studies wereconducted. Into these test tubes 2 ml of the extraction buffercontaining the released AHA were pipetted. The reactants were mixed, anda stable color was allowed to form. This procedure was also done for thestandard concentration solutions.

Absorbances for each of the solutions were measured at 515 nm on aPerkin-Elmer Lambda 3B UV/VIS Spectrophotometer. A calibration curve wascalculated from the standard concentration solutions. The concentrationsof the AHA were calculated from the absorbances and ratioed to theinitial surface area of the gel matrix.

Maximum loading of the AHA was desired for the prolonged releaserequired for effective control of the urease. This reason prompted theuse of the 16% AHA solution in contrast to other studies where lowerpercent loading solutions were used (Kou et al., 1988). The polymerseems to swell the most in the acetone solution. According to thePolymer Handbook, the ethanol solution is a solvent for both the MMA andAA, while acetone is not listed as such (Fuchs, 1989). The smallincrease in swelling of the gel in acetone might be attributed to theabsence of hydroxyl groups and presence of methyl groups, leading todecreased miscibility of the solvent with water and increasedmiscibility with the polymer. Because the acetone solution causedmaximum swelling of the polymer, the AHA was dissolved in this in orderto maximize the loading capacity of the matrix. The drug loading of thepolymer was approximately 13 w/w %.

Within the first 24 hours an initial burst of AHA was observed asrecorded for other systems in other studies (Kim and Lee, 1992a). Thegels released between 20% and 30% of their drug content. This initiallyhigh rate of release is probably due to a high surface concentration ofthe drug. According to Ritger and Peppas, zero-order release kineticscan be attained by any matrix geometry including the thin slab geometryused in this study (Ritger and Peppas, 1987). Therefore, the drugrelease was continued beyond 24 hours but, before continuing, the gelswere removed from the extraction media and redried to eliminate theburst effect and prolong the release by reducing the surfaceconcentration of AHA and creating a drug concentration gradient from thesurface to the center of the matrix (Korsmeyer and Peppas, 1984;Mueller, 1987).

FIG. 3 shows the release rate of the AHA from the MMA/AA matrix. For thesamples in both the pH 4.0 and 7.4 buffers, the rate decreases over the24 hr to 51 hr period and then levels off while the samples in the pH9.0 buffer exhibit a drop in release rate and then an increase. Thedecrease observed in all three can be explained by the burst effect.

FIG. 4 shows the cumulative release of the AHA from the matrix. Thecurves for pH 4.0 and 7.4 lie along the data's calculated linearregression line, suggesting a release directly proportional to time.There is a slight increase in the slope of the curve for the samples inpH 9.0 buffer after 50 hours due to the increased swelling, but thecurve is linear from this time until the conclusion of the experiment.The curves clearly indicate an increase in drug release at a pH of 9.0,a result of the increase in free volume in the matrix due to greaterchain mobility and subsequent increased swelling resulting in anincreased diffusivity of the solute. Only a slight increase in releasecan be observed in going from pH 4.0 to pH 7.4. The values shown in thegraph are ratioed to the surface area of the dry matrix for comparisonbetween samples. Therefore, the actual amount of AHA released by 105hours ranges from 469 μg at pH 4.0 to 1224 μg at pH 9.0. The amount ofAHA released at each interval ranges from 46 μg at pH 4.0 to 424 μg atpH 9.0. The concentration of the drug in the extraction medium at eachinterval ranges from 12 μg/ml at pH 4.0 to 106 μg/ml at pH 9.0.Therapeutic benefit can be achieved with a concentration of AHA as smallas 7.5 μg/ml; therefore, enough AHA is being released from the hydrogelto effectively inhibit the urease. The graph also shows that release ofthe drug continues to occur even after equilibrium swelling has beenreached. Kim and Lee found that solute release ceased as the swellingfront reaches the center of the matrix, suggesting a swelling-controlledrelease (Kim and Lee, 1992b).

FIG. 5 shows the percent release of the AHA from the MMA/AA hydrogel.The general trend is observed again that as the pH of the extractionmedium increases, the amount of drug released increases. At 105 hours,the percent of AHA released at pH 9.0 is almost 10%. Adding the initialrelease of approximately 20% to this value yields a total release ofapproximately 30%. This means that most of the drug remains in thepolymer for further release. The 30% drug release at 105 hours at pH 9.0is much less than the approximately 60% drug release exhibited by theHEMA/MA hydrogel used by Kou et al. (Kou et al., 1988). The relativelysmall amount of drug released must be a function of the composition ofthe polymer. The hydrophobic nature of the MMA in the matrix limits theswelling and therefore the release of the drug as compared to thehydrophilic nature of the HEMA polymer, which is more permeable to theextraction medium and swells more, allowing a greater diffusion of thesolute. For the MMA/AA hydrogel, as the drug depletion zone moves towardthe center of the matrix, the mobile hydrophobic chains can collapse andform a barrier to further drug release and extend the overall releaseduration (Mueller, 1987).

To reduce the release of AHA at acidic pH values, it would be apparentto one skilled in the art that the acrylic acid content of the polymercould be further reduced, making the polymer even more hydrophobic. Astronger barrier to aqueous environments would therefore result. Thecrosslink density of the polymer could also be increased. Chien hasshown that, as the crosslink density increases, the diffusivity ofsolute decreases (Chien, 1992). One final option might be to substituteacrylic acid with a comonomer that is less readily ionized. Swellingwould then be reduced.

EXAMPLE 4 Bacteria/Urease Study

Artificial urine was synthesized with the composition shown in Table 3.After mixing, the urine was filter-sterilized into a sterile containerusing a 0.2 μm pore size filtration system. A solution of thisartificial urine containing 750 μg/ml of AHA was prepared by dissolving0.0757 g of the AHA in 100 ml of the urine. This solution was thendiluted in series to yield artificial urine with AHA concentrations of375, 187.5, 75, and 7.5 μg/ml.

                  TABLE 3                                                         ______________________________________                                        Composition of artificial urine                                               Component     concentration g/liter                                           ______________________________________                                        CaCl.sub.2.2H.sub.2 O                                                                       0.65                                                            MgCl.sub.2.6H.sub.2 O                                                                       0.651                                                           NaCl          4.6                                                             Na.sub.2 SO.sub.4                                                                           2.3                                                             Na.sub.3 citrate.H.sub.2 O                                                                  0.65                                                            Na.sub.2 oxalate                                                                            0.02                                                            KH.sub.2 PO.sub.4                                                                           2.8                                                             KCl           1.6                                                             NH.sub.4 Cl   1.0                                                             Urea          25.0                                                            Creatinine    1.1                                                             ______________________________________                                    

Fifty milliliters of these solutions were sterilized by filtering themthrough a syringe filter with 0.2 μm pore size into a sterile container.

Proteus mirabilis were harvested from the Surgery/Urology clinic at theUniversity of Florida, Gainesville, Fla. These bacteria were cultured ona heart infusion agar (Difco Laboratories) for 48 hours at 37° C.Bacteria were aseptically harvested and suspended in a solution ofartificial urine not containing any of the urease inhibitor. Dilutionsof this suspension were made to 10,000, and a count of the bacteria wasmade on a microscopic counting grid. The initial concentration ofbacteria was back-calculated by using the Petroff-Hauser formula shownin equation two. ##EQU2## For the urine solutions containing the ureaseinhibitor and two control solutions (one containing bacteria and theother without), a series of six test tubes was set up. Into these testtubes, 5 ml of each separate urine solution was pipetted. A 0.5 mlvolume of nutrient broth was added to each of the test tubes to allowgrowth of the bacteria. Bacteria were then pipetted as aseptically aspossible into each of the test tubes except the control samples, whichcontained no bacteria. The final concentration of bacteria in solutionwas approximately 10¹¹ bacteria/ml. The test tubes were then mixed toobtain a homogenous mixture of bacteria and nutrient broth in the urineand placed in a 37° C. oven. The pH of each of the samples was measuredinitially and then at 2 hour intervals up to 12 hours. A final pHmeasurement was taken at 24 hours.

Artificial urine with concentrations of AHA corresponding to theconcentrations of AHA used for the drug release study was prepared sothat a correlation could be made between the amount released and theeffect of this concentration on the activity of the urease. FIG. 6 showsthe inhibitory effect of the AHA on the enzyme. Control samples with nobacteria present exhibited pH values ranging from 6.49 to 6.71 over the24-hour period. As the concentration of AHA increases, the artificialurine resists pH increase for a longer time and experiences a smalleroverall pH increase because there is more competition for the activesites on the urease molecule. More enzyme sites are blocked with the AHAand cannot react with the urea to form NH₃. With AHA concentrationsreleased ranging from 12 μg/ml to 106 μg/ml, enough drug is beingreleased to inhibit the urease. A high concentration of bacteria (10¹¹/ml) was used to test the effectiveness of the drug. In practice,bacteria concentrations of 10⁵ /ml or more are considered significant.With this lower, more clinically relevant concentration of bacteria, theeffect of the AHA should be more pronounced. The combination of AHA withthe quaternary amine methenamine, which is an antibacterial, may also beconsidered. The advantage to methenamine is that bacteria do not developa resistance to the drug, because the active form of the drug isformaldehyde (Krebs et al., 1984). Studies have also shown that thepresence of AHA increases the antibacterial activity of the methenamine(Musher et al., 1976).

EXAMPLE 5 Preparation of Coatings for Controlled Release

Two-inch long sections of 0.25-inch diameter natural latex rubber tubingwere oxidized in a solution composed of equal volumes of 30% hydrogenperoxide and concentrated formic acid at approximately 40° C. forapproximately three minutes. The time, temperature, and concentration ofoxidizing agents can be varied by one skilled in the art in order tochange the degree of oxidation. Optionally, the samples can be washedwith water and then soaked in a 1M KOH solution for 30 minutes afteroxidation. The samples were then washed with water. A solution of 3 g(0.5 to 5 g) acrylamide in 25 ml of water was prepared and thoroughlydegassed by bubbling nitrogen. To this was added 100 mg (10 to 300 mg)of ceric ammonium nitrate. The oxidized samples were placed into thissolution and the solution was then degassed again, capped, and stirredseveral hours (0.5 to 24 hours). The samples were removed and thoroughlywashed with water. The samples were found to have a very slipperycoating of polyacrylamide. The polyacrylamide was hydrolyzed topolyacrylic acid by soaking in 1M KOH for at least one hour. The sampleswere placed into a solution of 1% fluorescein dye in pH=10 phosphatebuffer solution for 12 hours. The samples were then soaked in pH=4buffer solution for 4 hours, then rinsed twice with pH=5 buffersolution. Two identical samples were selected and put into pH=6 and pH=8buffers, respectively. After one hour the higher pH solution wasobserved to have a strong green color, indicating release of the dye,while the lower pH solution showed only an extremely faint green color.

EXAMPLE 6 Additional Method for Preparing Coating for Controlled Release

Sections of rubber tubing were oxidized as in Example 5. These sectionswere then washed with water, then acetone, and allowed to air dry forone hour. A solution of 8 g SR2100, 2 g acrylic acid, 2 g THF, and 40 mgof benzoyl peroxide was prepared. The oxidized rubber samples weresoaked in this solution for one hour, removed, and hung vertically for afew minutes (about 1 to about 15 minutes, for example). The lower endsof the samples were then blotted with a dry tissue. The samples weresuspended horizontally on pins and placed in an oven at 80° C.overnight. The samples were then placed into a solution of 1.5% rosebengal dye in pH=11 buffer for 4 hours. The samples were removed andsoaked in pH=4 buffer for one hour, then returned to the dye solution.This process was repeated 4 times. Eventually, the rubber samplesacquired a very intense red color from the dye. The samples were soakedin clean buffer solution (pH=4, then pH=5) and dried in air. Twoidentical samples were selected and placed into pH=6 and pH=8 buffers,respectively. After one hour the higher pH buffer solution had adistinct red color while the pH=6 solution was colorless. After one weekthe pH=8 solution was very red and the pH=6 solution was stillcolorless.

It should be understood that the examples and embodiments describedherein are for illustrative purposes only and that various modificationsor changes in light thereof will be suggested to persons skilled in theart and are to be included within the spirit and purview of thisapplication and the scope of the appended claims.

References

Batich, C., J. Yan, M. Elsabee, C. Bucaria (1993) Macromolecules126:4675-4681.

Brannon-Peppas, L., N. A. Peppas (1989) "Solute and Penetrant Diffusionin Swellable Polymers. IX. The Mechanisms of Drug Release frompH-Sensitive Swelling-Controlled Systems," Journal of Controlled Release8:267.

Brannon-Peppas, L., N. A. Peppas (1990) "Dynamic and EquilibriumSwelling Behavior of pH-Sensitive Hydrogels Containing 2-HydroxyethylMethacrylate," Biomaterials 11:635.

Brazzini, A, W. R. Castaneda-Zuniga, C. C. Coleman, J. Hulbert, F.Castaneda, P. K. Reddy, D. W. Hunter, M. Darcy, T. Smith, K. Amplatz(1987) "Urostent Designs," Seminars in Interventional Radiology 4:26.

Breitenbach, H. M., R. P. Hausinger (1988) "Proteus mirabilis UreasePartial Purification and Inhibition by Boric Acid and Boronic Acids,"Biochem J. 250:917.

Bronstedt, H., J. Kopecek (1991) "Hydrogels for Site-Specific Oral DrugDelivery: Synthesis and Characterization," Biomaterials 12:584.

Chien, Y. W. (1992) Novel Drug Delivery Systems, Marcel Dekker, Inc.,New York.

DeMoor, C. P., L. Doh, R. A. Siegel (1991) "Long-Term Structural Changesin pH-Sensitive Hydrogels," Biomaterials 12:836.

Eckstein, E. C., L. Pinchuk, M. R. Van De Mark (1983) "A ResponsiveHydrogel Surface as a Means of Preventing Calcification in the UrinaryTract," Polymer Preprints 24:58.

Fowler, J. E. (1989) Urinary Tract Infection and Inflammation, Year BookMedical Publishers, Inc., Chicago.

Franco, G., C. DeDominicis, S. Dal Forno, F. Iori, C. Laurenti (1990)"The Incidence of Post-Operative Urinary Tract Infection in Patientswith Ureteral Stents," British Journal of Urology 65:10.

Fuchs, O. (1989) Polymer Handbook, John Wiley and Sons, Inc., New York.

Greenley, R. C. (1989) Polymer Handbook, John Wiley and Sons, Inc.

Griffith, D. P., S. Bragin, D. M. Musher (1976) "Dissolution of StruviteUrinary Stones: Experimental Studies in Vitro," Investigative Urology13:351.

Griffith, D. P., F. Yhonsari, J. H. Skurnick, K. E. James, and VeteransAdministration Cooperative Study Group (1988) "A Randomized Trial ofAcetohydroxamic Acid for the Treatment and Prevention ofInfection-Induced Urinary Stones in Spinal Cord Injury Patients,"Journal of Urology 140:318.

Griffith et al. (1991) "Randomized, double-blind trial of Lithostat(acetohydroxamic acid) in the palliative treatment of infection-inducedurinary calculi," Eur-Urol 20(3):243-247.

Hukins, D. W. L., R. L. Hackett (1983) "Catheter Encrustation byStruvite," British Journal of Urology 55:304.

Izumi, K, T. Kunihiko, Published European Patent Application No. EP 0065 884, published Dec. 1, 1982.

Kim, C., P. I. Lee (1992a) "Constant-Rate Drug Release from NovelAnionic Gel Beads with Transient Composite Structure," Proceed. Intern.Symp. Control Rel. Bioact. Mater. 19:162.

Kim, C., P. I. Lee (1992b) "Hydrophobic Anionic Gel Beads forSwelling-Controlled Delivery," Pharmaceutical Research 9:195.

Korsmeyer, R. W., N. A. Peppas (1984) "Solute and Penetrant Diffusion inSwellable Polymers. III. Drug Release from Glassy Poly(HEMA-co-NVP)Copolymers," Journal of Controlled Release 1:89.

Kou, J. H., G. L. Amidon, P. I. Lee (1988) "pH-Dependent Swelling andSolute Diffusion Characteristics of Poly(HydroxyethylMethacrylate-CO-Methacrylic Acid) Hydrogels," Pharmaceutical Research5:592.

Krebs, M., R. B. Halvorsen, I. J. Fishman, N. Santos-Mendoza (1984)"Prevention of Urinary Tract Infection During IntermittentCatheterization," Journal of Urology 131:82.

Kunin, C. M. (1987) Detection, Prevention, and Management of UrinaryTract Infections, Lea and Febiger, Philadelphia.

Lee, P. L. (1988) Controlled Release Systems: Fabrication Technology,CRC Press, Inc., Boca Raton.

Liedberg, H., T. Lundeberg, P. Ekman (1990) "Refinements in the Coatingof Urethral Catheters, Reduces the Incidence of Catheter-AssociatedBacteriuria," Eur. Urol. 17:236.

Mardis, H. K., R. M. Kroeger (1988) "Ureteral Stents," Urologic Clinicsof North America 15:471.

McLean, R. J. C., J. Downey, L. Clapham, J. C. Nickel (1990) "Influenceof Chondroitin Sulfate, Heparin Sulfate, and Citrate on Proteusmirabilis-Induced Struvite Crystallation in Vitro," Journal of Urology144:1267.

McLean, R. J. C., J. Downey, L. Clapham, J. W. L. Wilson, J. C. Nickel(1991) "Pyrophosphate Inhibition of Proteus mirabilis-Induced StruviteCrystallization in Vitro," Clinica Chimica Acta 200:107.

Mueller, K. F. (1987) "Release and Delayed Release of Water-SolubleDrugs from Polymer Beads with Low Water Swelling," In Controlled-ReleaseTechnology Pharmaceutical Applications, American Chemical Society,Washington, D.C.

Musher, D. M., D. P. Griffith, G. B. Templeton (1976) "FurtherObservations on the Potentiation of the Antibacterial Effect ofMethenamine by Acetohydroxamin Acid," Journal of Infectious Diseases133:564.

Nickel, J. C., J. Downey, J. W. Costerson (1992) "Movement ofPseudomonas aeruginosa Along Catheter Surfaces: A Mechanism inPathogenesis of Catheter-Associated Infection," Urology 39:93.

Odian, G. (1981) Principles of Polymerization, John Wiley and Sons, NewYork.

Olson, M. E., J. C. Nickel, J. W. Costerson (1989) "Animal Model ofHuman Disease Infection-Induced Struvite Urolithiasis in Rats," AmericanJournal of Pathology 135:581.

Park, K (1988) "Enzyme-Digestible Swelling Hydrogels as Platforms forLong-Term Oral Drug Delivery: Synthesis and Characterization,"Biomaterials 9:435.

Pearce, R. S. C., L. R. West, G. T. Rodeheaver, R. F. Edlich (1984)"Evaluation of a New Hydrogel Coating for Drainage Tubes," AmericanJournal of Surgery 148:687.

Pepper, K. et al. (1952) J. Chem. Soc. 3129.

Ramsay, J. W. A., R. A. Miller, P. R. Crocker, B. J. Ringrose, S. Jones,D. A. Levison, H. N. Whitfield, J. E. A. Wickham (1986) "An ExperimentalStudy of Hydrophilic Plastics for Urological Use," British Journal ofUrology 58:70.

Reid, G., C. Tieszer, R. Foerch, H. J. Busscher, A. E. Khoury, A. W.Bruce (1993) "Adsorption of ciprofloxacin to urinary catheters andeffect on subsequent bacterial adhesion and survival," Colloids andSurfaces B: Biointerfaces 1:9-16.

Ritger, P. L., N. A. Peppas (1987) "A Simple Equation for Description ofSolute Release II. Fickian and Anomalous Release from SwellableDevices," Journal of Controlled Release 5:37.

Robert, C. C. R., P. A. Buri, N. A. Peppas (1987) "Influence of the DrugSolubility and Dissolution Medium on the Release fromPoly(2-Hydroxyethyl Methacrylate) Microspheres," Journal of ControlledRelease 5:151.

Saunders, K. (1988) Organic Chemistry of Polymers--2nd ed., Chapman andHall Pub., New York.

Soloman, D. D., R. J. Sheretz (1987) "Antibiotic Releasing Polymers,"Journal of Controlled Release 6:343.

Soloman, D. D., U.S. Pat. No. 4,999,210, issued Mar. 12, 1991.

Soriano, F., C. Ponte, M. Santamaria, R. Fernandez-Roblas (1987)"Struvite Crystal Formation by Corynebacterium Group D2 in Human Urineand Its Prevention by Acetohydroxamic Acid," Eur. Urol. 13:271.

Stamm, W. E. (1991) "Catheter-Associated Urinary Tract Infections:Epidemiology, Pathogenesis, and Prevention," American Journal ofMedicine 91:3B-65S.

Swartz, R., J. Messana, C. Holmes, J. Williams (1991) "Biofilm Formationon Peritoneal Catheters Does Not Require the Presence of Infection,"Trans. Am. Soc. Artif. Intern. Organs 37:626.

Takeuchi, H., K. Kobashi, O. Yoshida (1980) "Prevention of InfectedUrinary Stones in Rats by Urease Inhibitor: A New Hydroxamic AcidDerivative," Investigative Urology 18:102.

Tarcha, P. J. (1991) Polymers for Controlled Delivery, CRC Press, BocaRaton.

Whitbourne, R. J., M. A. Mangan, Published European Patent ApplicationEP 0 426 486, published May 8, 1991.

Wu, K. J., X. Q. Li, S. J. Yao (1985) "Induction and Inhibition ofStruvite Bladder Stones in Rats," Urolithiasis and Related ClinicalResearch Proceedings of the Fifth International Symposium!:957.

We claim:
 1. A medical device for controlling a bacterial infectionwhich causes a change in the pH of the environment of the device,wherein said device comprises a pH-sensitive polymer matrix containing abiologically active agent, said agent being a bacterial control agent oran antibacterial agent, said agent further being released from saidpolymer matrix upon said change of pH, wherein said device is selectedfrom the group consisting of sutures, contact lenses, catheters,indwelling stents, shunts or tubes, gastrointestinal tubes, respiratorytubes, penile implants, heart pacemakers, and neural shunts.
 2. Thedevice of claim 1 wherein the device is a gastrointestinal tube and theagent released is selected from the group consisting of an anti-acid,famotidine, ranitidine, and omeprazole.
 3. A medical device forcontrolling a bacterial infection which causes a change in the pH of theenvironment of the device, wherein said device comprises a pH-sensitivepolymer matrix containing a biologically active agent, said agent beinga bacterial control agent or an antibacterial agent, said agent furtherbeing released from said polymer matrix upon said change of pH, whereinsaid pH-sensitive polymer matrix containing said biologically activeagent is fabricated by folding an interpenetrating network comprisingboth plastic or elastomeric polymer and a pH sensitive polymer formed insitu from monomers soaked into said plastic or elastomeric polymer. 4.The device of claim 3 wherein said plastic or elastomeric polymer isselected from the group consisting of polyester, polyurethane, silicon,polyolefin copolymers, and oxidized rubber.
 5. The device of claim 4wherein the rubber is in the form of a natural rubber latex catheter,and the monomer is a mixture of a long chain diol methacrylate andacrylic acid monomers.
 6. A medical device for controlling a bacterialinfection which causes a change in the pH of the environment of thedevice, wherein said device comprises a pH-sensitive polymer matrixcontaining a biologically active agent, said agent being a bacterialcontrol agent or an antibacterial agent, said agent further beingreleased from said polymer matrix upon said change of pH, wherein saidpH-sensitive polymer matrix containing said biologically active agent isfabricated by polymerizing acrylamide monomers on the surface ofoxidized natural latex rubber to form a polyacrylamide coating on saidoxidized latex rubber, and then hydrolyzing the polyacrylamide to form apolyacrylic acid coating.